In FY2013: 1) We have worked toward a better understanding of prion structure by initiating the application of new (to our lab) biochemical, immunological, spectroscopic, electron microscopic, and computational approaches to defining the structure of infectious prions. We have developed new models of prion structure is being built and evaluated based on our own new data, as well as published reports. These models are based on parallel-in-register beta sheet architectures, partial versions of which have been proposed by others. These developments are in progress and are expected to lead to significant discoveries soon. 2) We have assessed the role of normal prion protein in responses to stimulators of toll-like receptor ligands and have not found any significant effects. 3) We have probed the role of normal prion protein in the experimental autoimmune encephalomyelitis in mice of the C57/BL background and found no significant effect.